Basal cell carcinoma is presently treated by surgery. Each lesion, together with all surrounding and underlying tissue (dermis, epidermis, and subdermis), is cut out. In some instances, surgery, while necessary for the patient's welfare, may put the patient at risk in some other respect (for example, a lesion on a patient's temple whose removal (resection) may jeopardize the patient's health). Squamous cell tumours are also treated the same way as are other forms of cancer in the skin and exposed tissue. Furthermore, other conditions and diseases of the skin and exposed tissue are treated the same way or in ways that cause discomfort to the patient, for example melanoma, genital warts, cervical cancer, HPV (Human Papilloma Virus).
Actinic keratoses lesion is dealt with similarly. Additionally, liquid nitrogen has been used to remove the lesion.
These diseases and conditions are usually found in the epidermis (at least for the most part extending into the dermis and through Stratum Corneum).
Hyaluronic acid is a naturally occurring glycosaminoglycan. Its molecular weight may vary from 50,000 dalton upwards, and it forms highly viscous solutions. As regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty; when the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method etc. The acid occurs in animal tissue, e.g. spinal fluid, ocular fluid, synovial fluid, cockscombs, skin, and also in some streptococci. Various grades of hyaluronic acid have been obtained. A preparation with an allegedly high degree of purity and alleged to be entirely free from side effects, is a non-inflammatory form described in U.S. Pat. No. 4,141,973; this preparation is said to have a molecular weight exceeding 750,000 dalton, preferably exceeding 1,200,000 dalton and is suggested for therapeutic use in various articular conditions.
U.S. Pat. No. 4,801,619 relates to hyaluronic acid,having a molecular weight of about 3.times.10.sup.6 dalton or more, administered intra-articularly which is prone to decrease the proteoglycan content of synovial fluid to almost normal levels. According to this patent, this indicates a positive effect on the proteoglycan metabolism of a joint. According to the patent, this is applicable both to inflammatory conditions and to degeneration caused by treatment with symptomatics, such as corticosteroid preparations. It is thus clear that a sufficiently high molecular weight of the hyaluronic acid is alleged to counteract side effects that might be caused by corticosteroids or other symptomatics producing similar effects. When corticosteroids are applied, the amount of hyaluronic acid in the synovial cavity will, according to the patent, increase substantially and, according to the inventors, their hyaluronic acid preparations have a very positive effect on such clinical symptoms as pain, swelling, and lameness.
The patent states that the objectives of the invention are attained by intra-articular administration of an effective amount of hyaluronic acid with a mean molecular weight exceeding 3.times.10.sup.6 dalton, preferably exceeding 4.times.10.sup.6 dalton; usually the molecular weight will not exceed 7.times.10.sup.6 dalton. The dosage of hyaluronic acid administered is stated to be preferably within the range of 5 mg-80 mg. The amount of solution given at each administration is generally less than 60 ml, e.g. less than 20 ml. of an aqueous solution of the acid or its salt. It is convenient to administer the acid dissolved in water (&lt;2% w/w, buffered to physiological pH), for instance in the form of a water-soluble sodium salt. The exact amount will depend on the particular joint to be treated.
The Merck Index Specifies that Hyaluronic Acid has a Molecular Weight within the range pf 50,000 to 8.times.10.sup.6 depending on source, methods of preparation, and methods of determination. The Merck Publication teaches hyaluronic acid as a surgical aid (ophthalmological).
U.S. Pat. No. 4,808,576 purports to teach that hyaluronic acid, an agent well known for reducing the sequelae of trauma in mammalian joint tissue when applied directly to the traumatized tissue, will be carried to such traumatized tissue by the mammal's natural processes if applied at a site remote from the traumatized tissue. Thus, hyaluronic acid in any therapeutically acceptable form can, according to the Patent, be administered by the typical remote routes including intravenous, intramuscular, subcutaneous, and topical.
This, the patent alleges, makes the utilization of hyaluronic acid much more convenient and attractive. For instance, the treatment of arthritis in horse or human joints with hyaluronic acid, according to the patent, no longer requires more difficult intra-articular injections.
U.S. Pat. No. 4,725,585 relates to a method of enhancing or regulating the host defence of a mammal, said method comprising administering to a mammal a therapeutically effective amount of hyaluronic acid.
At column 1, lines 43-46, the patent provides that the invention was based on the unexpected discovery that administration of hyaluronic acid to mammals results in a considerable increase in the defence.
The hyaluronic acid employed in the patent was Healon provided by Pharmacia AB, Uppsala, Sweden (Pharmacia AB is also entitled to the benefit of U.S. Pat. No. 4,141,973). The patent provides at column 4, line 19 that because a patient's infections had been hard to treat, instead of just hyaluronic acid being administered to the patient to increase the patient's defence, the patient was given hyaluronic acid and an antibiotic. While the patent states that the antibiotic was given in combination with hyaluronic acid, in fact because the hyaluronic acid was administered subcutaneously and because the patient was a heart patient, one skilled in the art would understand that any antibiotic administered, while possibly administered simultaneously was definitely administered separately intravenously (probably) or intramuscularly (less probably). Thus, (most probably) the hyaluronic acid administered, according to the teachings of this patent, was administered in order to prevent possible development of infections (increase the host's defence) and not for any other reason.
U.S. Pat. No. 4,636,524 discloses cross-linked gels of hyaluronic acid, alone and mixed with other hydrophilic polymers and containing various substances or covalently bonded low molecular weight substances and processes for preparing them. These products are alleged to be useful in numerous applications including cosmetic formulations and as drug delivery systems.
The patent further states that as hyaluronic acid is known to be a biologically tolerable polymer in the sense that it does not cause any immune or other kind of response when introduced into a human body, the cross-linked hyaluronic acid gels can be used for various medical applications. The cross-linked gels modified with other polymers or low molecular weight substances, it is alleged, can be used as drug delivery devices. For example, the inventors are alleged to have found that heparin introduced in a cross-linked hyaluronic acid gel retained its antithrombogenic activity.
The inventors also allege that they have also found that cross-linked gels of hyaluronic acid can slow down the release of a low molecular weight substance dispersed therein but not covalently attached to the gel macromolecular matrix.
U.S. Pat. No. 4,736,024 purports to teach new medicaments for topical use containing:
(i) an active pharmacological substance or a mixture of pharmacological substances, either active or suitable for topical administration and PA1 (ii) a topical vehicle which comprises hyaluronic acid or a molecular fraction of hyaluronic acid or a salt of the same with an alkaline metal, an alkaline earth metal, magnesium, aluminium, ammonium, or a pharmacological substance optionally together with additional conventional excipients for pharmaceutical preparations for topical use. PA1 The patent provides at column 13, lines 5 to 31: "The vehicling action of the hyaluronic esters also applies to associated medicaments of the type mentioned above in which the active substance acts not only topically or by nasal or rectal absorption, for example by nasal sprays or preparations for inhalation for the oral cavity or the pharynx, but also by oral or parenteral route, for example by intramuscular, subcutaneous or intravenous route, as it favors absorption of the drug into the application site. The new medicaments can therefore be applied, apart from in the fields already mentioned, in practically all sectors of medicine, such as internal medicine, for example in pathologies of the cardiovascular system, in infections of the respiratory system, the digestive system, the renal system, in diseases of an endocrinological nature, in oncology, in psychiatry etc., and may also be classified therefore from the point of view of their specific action, being perhaps anesthetics, analgesics, anti-inflammatories, wound healers, antimicrobics, adrenergic agonsits and antagonists, cytostatics, antirheumatics, antihypertensives, diuretics, sexual hormones, immunostimulants and immunosuppressants, for example, one of the drugs having the activity already described for the therapeutically active alcohols to be used as esterifying component according to the present invention, or for the therapeutically active bases used for the salification of the free carboxylic groups." PA1 1. Modulation of Immunity in Cancer Patients by Prostaglandin Antagonists, Immunity to Cancer II, Alan R. Liss, Inc.; and PA1 2. Goodwin, J. S., (1981) Prostaglandin E and Cancer Growth Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors, Augmentive Agents in Cancer Therapy, Raven Press, New York. PA1 Set up stirring apparatus using a 3 liter stainless steel beaker PA1 Add Water, Glycerin, Benzyl Alcohol and Liquid Wax DICDD, stir and mix for 10 minutes PA1 Add Diclofenac Sodium and stir for 30 minutes to dissolve PA1 Add Sodium Hyaluronate and stir for 90 minutes PA1 Set up stirring apparatus using a 400 ml stainless steel beaker PA1 Add Water, Glycerin, Benzyl Alcohol, Liquid Wax DICDD, and stir to mix thoroughly for 10 minutes PA1 Add Diclofenac Sodium and stir for 20 minutes to dissolve PA1 Very slowly add Carbopol 934, avoid getting lumps PA1 set up stirring apparatus using a 4 litre stainless steel beaker PA1 add water, Glycerine, and Benzyl Alcohol; stir to mix PA1 add Diclofenac Sodium and stir for 30 minutes PA1 then add the Sodium Hyaluronate and stir for 90 minutes PA1 initially, stir at a high torque but avoid splashing; as the gel thickens, stir at a lower torque PA1 set up stirring apparatus using a 3 litre stainless steel beaker PA1 add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix PA1 add Diclofenac Sodium and stir for 30 minutes to dissolve PA1 add Hyaluronate Sodium slowly and stir initially at a high speed, but avoid splashing PA1 after addition, stir at a slower speed for 90 minutes; the slower speed reduces the formation of air bubbles PA1 the result is a clear, transparent, viscous gel PA1 Set up stirring apparatus using a 2 liter stainless steel beaker, PA1 Add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix, PA1 Add Diclofenoc Sodium and stir for 30 minutes to disolve, PA1 Add Hyularonate Sodium slowly and stir initially at a high speed, but avoid splashing, PA1 After addition, stir at a slower speed for 90 minutes, the slower speed reduces the formation of air bubbles, PA1 The results is a clear transparent, viscous gel. PA1 Set up stirring apparatus using a 300 ml stainless steel beaker, PA1 Add Steril Water and Meglumine, and stir for 10 minutes, PA1 Add Ibuprofen and stir for 15 minutes, PA1 Add Benzyl Alcohol, followed by Glycerin and stir for 15 minutes, PA1 Finally, add Hyaluronate Sodium slowly and stir initially at a high torque to mix, but avoid splashing, PA1 As the gel thickens, stir at a slow speed for 90 minutes. PA1 Set up stirring apparatus using a 300 ml stainless steel beaker, PA1 Add 200 ml of sterile water, PA1 Add 8 grams of Meglumine and dissolve, PA1 Very slowly add 4 grams of Piroxicam and stir for 20 minutes, PA1 Slowly add 5 grams of Hyaluronate Sodium and stir at high target, PA1 Stir for 90 minutes at a slower speed PA1 A clear yellowish transparent gel PA1 A--Add all the ingredients of the oily phase A into a 4 liter stainless steel beaker, melt at 55.degree. C., finally heat to 75% when Aqueous Phase B is ready PA1 B--Into a 3 liter stainless stell beaker, add 1950 ml water, set up, the stirring apparatus, add the Meglumine, stir to dissolve for 10 minutes, PA1 Slowly add Ibuprofen, stir to dissolve for 20 minutes, PA1 Very slowly add Sodium Hyaluronate and stir colf for one hour to dissolve all the Sodium Hyaluronate, PA1 Finally, heat to 75.degree. C., with stirring for a total time of 30 minutes, PA1 Remove the heat source and stir with a strong vortex for one hour, PA1 When the temperature has cooled down to 45.degree. C. add preservative Suttocide A, PA1 Continue stirring at a slower speed until thetemperature is 35.degree. C., PA1 At 35.degree. C. remove the propeller, pour into 50 ml jars. PA1 Set up stirring apparatus using a 4 liter stainless steel beaker. PA1 Add water, Glycerin, Benzyl Alcohol and Liquid wax DICDD and stir to mix thoroughly for 10 minutes PA1 Add Diclofenac Sodium and stir for 30 minutes to dissolve. PA1 Slowly add Hyaluronate Sodium, stirring at a high torque initially during addition. PA1 After addition stir at a slower speed for 90 minutes. PA1 A white opaque viscous gel is formed. PA1 Set up stirring apparatus using a 3 liter stainless steel beaker. PA1 Add water, Glycerin, Benzyl Alcohol and Liquiwax DICDD, stir to mix for 10 minutes. PA1 Add Diclofenac Sodium and stir for 30 minutes to dissolve. PA1 Add Sodium Hyaluronate and stir for 90 minutes. PA1 A.--Add all the ingredients of the oily phase into a 4 liter stainless steel beaker, melt at 55.degree. C., finally heat to 75.degree. C. when aqueous phase is ready (at 75.degree. C.) to pour in. PA1 B.--Into another 4 liter stainless steel beaker, add 1950 ml water. PA1 Set up the stirring apparatus and add the Meglumine PA1 Stir to dissolve with high torque, then slowly add Ibuprofen PA1 When the Ibuprofen is dissolved, slowly add Sodium Hyaluronate PA1 Stir cold for one hour to dissolve all the ingredients PA1 Finally heat to 75.degree. C. and stir thoroughly throughout a 30 minute period PA1 Slowly pour B into A (both at 75.degree. C.) with stirring PA1 Immediately remove the hot plate (heat) and stir PA1 Stir with a strong vortex for one hour PA1 When the temperature is 45.degree. C., add the preservative Suttocide A PA1 Stir for about an hour to cool to 35.degree. C. PA1 At 35.degree. C. remove the propeller and pour into 50 ml tubes PA1 Pour 50 grams of the cream into each tube PA1 Set up stirring apparatus using a 4 liter stainless steel beaker PA1 Add water, stir with a strong vortex, then add sodium Hyoluronate slowly PA1 Then immediately add the Banamine, stir the mixture for 4 hours. PA1 a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from the group consisting of the following: PA1 i) less than about 1% sulphated mucopolysaccharides on a total weight basis; PA1 ii) less than about 0.4% protein on a total weight basis; PA1 iii) less than about 100 ppm iron on a total weight basis; PA1 iv) less than about 10 ppm lead on a total weight basis; PA1 v) less than 0.00166% glucosamine; PA1 vi) less than 0.0166% glucuronic acid; PA1 vii) less than 0.0166% N-acetylglucosamine; PA1 viii) less than 0.00166% amino acids; PA1 x) a UV extinction coefficient at 257 nm of less than about 0.23; PA1 xi) a UV extinction coefficient at 280 nm of less than 0.19; and PA1 xii) a pH within the range of 7.5-7.7 PA1 "(a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,000--that is, a limiting viscosity number greater than about 1400 cm.sup.3 /g., and preferably greater than about 2000 cm.sup.3 /g.; PA1 (b) a protein content of less than 0.5% by weight; PA1 (c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength; PA1 (d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes; PA1 (e) a molar optical rotation of a 0.1-0.2% sodium hyaluronate solution in physiological buffer of less than -11.times.10.sup.3 degree--cm.sup.2 /mole (of disaccharide) measured at 220 nanometers; PA1 (f) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humour, no haze or flare in the vitreous, and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1% solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being PA1 (g) sterile and pyrogen free and PA1 (h) non-antigenic." PA1 Diclofenac with Hyaluronic Acid Dose: Approximately 2 g, three times daily Route: Topical PA1 (W1) Voltarol Emulgel, Diclofenac diethylammonium salt 1.16 g aqueous gel (Geigy) Dose: Approximately 2 g, three times daily Route: Topical (W1)
Applicants are also aware of published Japanese Patent Document 61000017, dated 86/01/06, whose English abstract of disclosure states that the Japanese Patent Document relates to the use of hyaluronic acid or cross-linked hyaluronic acid or their salts as the active ingredient for inhibiting carcinoma metastasis.
According to the purported abstract of the patent, more that 1.0% of hyaluronic acid is dissolved in alkaline aq. soln. and pref. more than 50% of H.sub.2 O sol. org. solvent. eq. alcohol, acetone, dioxane, against total soln. is added. Preferably the pH is 12-14. Then multifunctional epoxy cpd. is added and reacted at 10-60 deg. C., pref. at 20-40-deg. C. for 24 hrs. Cross-linking ratio of crosslinked hyaluronic acid or its salt is regulated by changing mol ratio of hyaluronic acid or its salt and multifunctional epoxy cpd. Pref. hyaluronic acid used has intrinsic viscosity 0.2-30,m.w. 4000-2000000. The hyaluronic acid is allegedly used in several dosage forms. Clinical dose for adult is alleged to be normally, as hyaluronic acid or cross-linked hyaluronic acid, 25 mg-5 g/day (p.o.) and 10 mg-2.5 g/l dose (inj). The abstract alleges that the advantage is that the hyaluronic acid has no side effects as may other anti-cancer drugs and has an analgesic and a tissue restoration effect.
European Patent Application 0295092 purports to teach a vehicle together with fragments of hyaluronic acid for delivering of the fragments of hyaluronic acid into the skin to reach the dermal layer of the skin to increase the development of blood vessels for stimulating hair growth or regrowth. The preferred fragments of hyaluronic acid are polysaccharides containing from 7 to 25 monosaccharide units. The patent provides that it is apparent that the larger the fragments of hyaluronic acid, the greater the difficulty there is in delivering the fragments to the dermal layer of the skin, unless there is also present in the composition a means for enhancing the activity of said fragments.
The combination may thus include a means for enhancing the activity of the fragments of hyaluronic acid, especially to improve their penetration through the skin following topical application. Some activity enhancers, it is alleged, also function as vehicles for the fragments of the hyaluronic acid.
Some activity enhancers are also alleged to possess the ability to stimulate or increase hair growth. Minoxidil is asserted among others to be such an activity enhancer. Thus both the fragments of hyaluronic acid and minoxidil are alleged to stimulate hair growth both delivered by a vehicle.
European Patent Application 0179442 asserts that where free radicals are formed in considerable quantities, hyaluronic acid is broken down or degraded before the hyaluronic acid has given the desired effect.
Canadian Letters Patent 1,240,929 teaches the combination of chondroitin sulfate compound and a hyaluronate to protect both human and animal cell layers and tissue subject to exposure to trauma.
European Patent Application 0208623 purports to teach hyaluronic acid as "une augmentation de l'activite de certaines proteases". It also purports to teach the use of hyaluronic acid for treating connective tissue diseases, including malignant tumours and cardiovascular disorders.
European Patent Application 270317 purports to teach the combination of an antiviral agent lacking inhibitory action and a compound [for example, hyaluronic acid] possessing cell fusion inhibitory activity and/or virus-adsorption inhibitory activity for treating disease carried by a virus.
U.S. Pat. No. 4,840,941 purports to teach the use of an effective amount of hyaluronic acid as the active agent for the treatment of retroviruses in association with a pharmaceutically acceptable carrier, diluent, or excipient.
U.S. Pat. No. 4,851,521 and European Patent Application 0265116 both describe hyaluronic acid fractions, the making thereof and cross-linked esters of hyaluronic. U.S. Pat. No. 4,851,521 describes esters of hyaluronic acid incorporated into pharmaceutical preparations as the active ingredient and as vehicles for ophthamological medicines for topical use (See column 11, lines 35 to 42; and column 12, lines 62 to column 13, line 3) and in suppositories for a systemic effect due to the effect of transcutaneous absorption, such as in suppositories.
There have been extensive studies to determine the defect in immune function that allows a tumour cell to develop. It was postulated initially by Jerne, and subsequently by Burnett, that the immune system's major role was that of immunological surveillance to destroy abnormal cells. The concept of surveillance, while somewhat simplistic, remains an accepted concept for the elaborate mechanism of immune recognition and function that is present in the higher species--mammals.
It has then been postulated that tumours develop because of local or generalized immune suppression. However, as pointed out by Moller, if general immune suppression occurs, it is only certain types of neoplastic disorders that develop, mainly those of the lympho-reticular system. This observation is correct and represents a major challenge to the immune surveillance theory unless a specific reason can be shown as to why the individual cancer cell can develop plus individually evade the immune system.
It was demonstrated experimentally in 1974 that defects of macrophage function may exist in neoplastic disease.
The initial experiments found suppressor cells to be part of the immune system; these were either of the T-cell type of the macrophage cell system. There was presence demonstrated in neoplasia, chronic bacterial infection, recovery from massive injury and chronic fungal infection.
There has been repeated demonstration in experimental animals that the macrophage cell function is altered in neoplastic disease. The macrophages in the animal's systems appeared "blocked" in their function. Generally when removed from the in vivo situation, washed in saline and cultured, they could perform normally. This block has been shown to be related to the excessive production of prostaglandin by neoplastic tissue or by the macrophage itself. Similarly, the N.K. cells (which are said to be primitive or immature macrophages and which may be involved in cancer defence) are also blocked.
In the basic research efforts in the latter '70s and the early '80's, there existed considerable confusion as to what role immunotherapy should take in cancer. Activation or "hyping" of macrophages was thought to be important. However, in an examination by Romans and Falk of peritoneal macrophages obtained from patients with neoplastic disease, there was definite evidence that these macrophages were already activated yet were co-existing with cancer cells and not causing their destruction.
It has recently been shown by several independent investigators that the malfunction of macrophages or the putitive block is due to excessive prostaglandin and that this can be altered in tissue culture by corticosteroids, ASA, and the non-steroidal anti-inflammatory drugs, i.e. indomethacin and naproxen (Naprosyn.TM.). Again, it was repeatedly demonstrated that in animal tumours these substances could alter the response to neoplastic cells and that various combinations of these substances employed with immune enhancing agents could produce very credible success in eliminating experimental tumours. Lala and co-workers combined Indomethacin therapy with Interleukin 2 and showed that this could effect a cure with experiment neoplasm.
There were continued problems with the use of any of these agents in the actual human in vivo experience. All of the non-steroidal anti-inflammatory agents (NSAID) produced major toxicity in terms of gastro-intestinal, neurological, and other areas. Thus, the basis of the present approach is that, under general circumstances, with the use of these agents in human disease in sufficient amounts, the drug will penetrate to any pathological tissue to alter therapeutically local prostaglandin production. While intravenous preparations of Indomethacin (and now of other agents) exist, using these drugs alone produces prohibitive side effects in human subjects. Therefore, only insufficient amounts can be brought into the body to effect more than occasional responses in neoplasm.
However, the majority of the evidence is present to indicate and therefore, it can be postulated that the basis for neoplastic development and how the initial cell "sneaks by" the immune surveillance mechanism relates to its production of prostaglandin. One need postulate only one mutation to alter the amount of prostaglandin synthesis produced by cells when they become "malignant" to establish a mechanism of blocking out the initial cell in any immune reaction, i.e. the macrophage. It therefore became essential to develop a combination of NSAIDs for clinical use to produce a major improvement in response in neoplastic disease and other conditions where excessive prostaglandin synthesis represents the basis of the pathogenesis of this disease state, i.e. arthritis and various others of the so-called connective tissue inflammatory disorders and/or auto-aggressive diseases.
See also:
U.S. Pat. No. 4,711,780 teaches a pharmaceutical composition comprising Vitamin C, a zinc salt, and a sulfur amino acid for treating surface epithelium for epithelium regeneration. Hyaluronic acid may be added for applications in the reproductive tract.
Because of the side effects of the use of non-steroidal anti-inflammatory drugs (major toxicity in terms of gastro-intestinal, neurological, and other areas),use thereof should also be restricted (if possible) to the area of use without delivery to other areas which are not in need of treatment. Thus, if useful amounts of the non-steroidal anti-inflammatory drugs could be delivered to a site in need thereof without carriage of substantial amounts away from the site to be treated, then the use of a non-steroidal anti-inflammatory drug may have many other useful applications.